Post-translational regulation of TGF-β receptor and Smad signaling.

Department of Cell and Tissue Biology, Programs in Cell Biology and Developmental Biology, University of California, San Francisco, CA, USA.

Abstract

TGF-β family signaling through Smads is conceptually a simple and linear signaling pathway, driven by sequential phosphorylation, with type II receptors activating type I receptors, which in turn activate R-Smads. Nevertheless, TGF-β family proteins induce highly complex programs of gene expression responses that are extensively regulated, and depend on the physiological context of the cells. Regulation of TGF-β signaling occurs at multiple levels, including TGF-β activation, formation, activation and destruction of functional TGF-β receptor complexes, activation and degradation of Smads, and formation of Smad transcription complexes at regulatory gene sequences that cooperate with a diverse set of DNA binding transcription factors and coregulators. Here we discuss recent insights into the roles of post-translational modifications and molecular interaction networks in the functions of receptors and Smads in TGF-β signal responses. These layers of regulation demonstrate how a simple signaling system can be coopted to exert exquisitely regulated, complex responses.

The TGF-β signaling pathway is outlined in thick gray lines, whereas the endosomal recycling pathway and lipid rafts-caveolae degradation pathway are indicated by green and blue lines, respectively. Binding of ligand stabilizes the heteromeric complex of TβRII and TβRI receptors, resulting in activation of TβRI through phosphorylation of its GS domain by TβRII. R-Smads are then activated by TβRI with SARA as scaffold, and form trimeric complexes with Smad4 that translocate into the nucleus, where they direct transcription responses of target genes. Activated receptor complexes are also internalized through lipid rafts and caveolae, where they are poly-ubiquitylated by E3 ubiquitin ligases recruited by Smad7 and destined for degradation. Various regulators of functional TGF-β receptor complexes are schematically shown. Inhibitory mechanisms are listed in a red box with blunt-headed lines, whereas those that enhance the complexes formation are listed in a green box with arrows.

Thick gray lines illustrate Smad signaling, whereas nucleocytoplasmic shuttling and degradation of Smads are indicated by solid and dashed light-blue lines, respectively. Activation of R-Smads by TβRI facilitates the formation of trimeric R-Smad/Smad4 complexes, which are imported into the nucleus to regulate transcription of target genes. R-Smad phosphorylation at various sites besides the C-terminus prevents nuclear import of the complexes, or favors degradation of the complexes, resulting in termination of signaling. Diverse regulators modulate the activated Smad complexes inside the nucleus, and control the balance between complex formation and dissociation, thus determining the overall signaling outcome in a context-dependent manner. Inhibitory mechanisms are listed in a red box with blunt-headed lines, and those that promote the indicated processes are listed in a green box with arrows.